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ア セ ト 酢 酸 メ チ ル の マ ウ ス を 用 い た 経口投与によるがん原性試験(混水試験)報告書
試験番号:0449
APPENDICES
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(Study No. 0449)
APPENDICES APPENDIX A 1 IDENTITY OF METHYL ACETOACETATE IN THE 2-YEAR
DRINKING WATER STUDY APPENDIX A 2 STABILITY OF METHYL ACETOACETATE IN THE 2-YEAR
DRINKING WATER STUDY APPENDIX A 3 CONCENTRATION OF METHYL ACETOACETATE IN
FORMULATED WATER IN THE 2-YEAR DRINKING WATER STUDY
APPENDIX A 4 STABILITY OF METHYL ACETOACETATE IN FORMULATED
WATER IN THE 2-YEAR DRINKING WATER STUDY APPENDIX B 1 CLINICAL OBSERVATION: MALE APPENDIX B 2 CLINICAL OBSERVATION: FEMALE APPENDIX C 1 BODY WEIGHT CHANGES: MALE APPENDIX C 2 BODY WEIGHT CHANGES: FEMALE APPENDIX D 1 FOOD CONSUMPTION CHANGES: MALE APPENDIX D 2 FOOD CONSUMPTION CHANGES: FEMALE APPENDIX E 1 WATER CONSUMPTION CHANGES: MALE APPENDIX E 2 WATER CONSUMPTION CHANGES: FEMALE APPENDIX F 1 CHEMICAL INTAKE CHANGES: MALE APPENDIX F 2 CHEMICAL INTAKE CHANGES: FEMALE APPENDIX G 1 HEMATOLOGY: MALE APPENDIX G 2 HEMATOLOGY: FEMALE APPENDIX H 1 BIOCHEMISTRY: MALE APPENDIX H 2 BIOCHEMISTRY: FEMALE
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(Study No. 0449)
APPENDICES (CONTINUED) APPENDIX N 1 NUMBER OF ANIMALS WITH TUMORS AND NUMBER OF
TUMORS-TIME RELATED: MALE APPENDIX N 2 NUMBER OF ANIMALS WITH TUMORS AND NUMBER OF
TUMORS-TIME RELATED: FEMALE APPENDIX O 1 HISTOPATHOLOGICAL FINDINGS: NEOPLASTIC LESIONS:
MALE APPENDIX O 2 HISTOPATHOLOGICAL FINDINGS: NEOPLASTIC LESIONS:
FEMALE APPENDIX P 1 NEOPLASTIC LESIONS-INCIDENCE AND STATISTICAL
ANALYSIS: MALE APPENDIX P 2 NEOPLASTIC LESIONS-INCIDENCE AND STATISTICAL
ANALYSIS: FEMALE APPENDIX Q1 HISTOPATHOLOGICAL FINDINGS: METASTASIS OF TUMOR:
MALE: ALL ANIMALS APPENDIX Q 2 HISTOPATHOLOGICAL FINDINGS: METASTASIS OF TUMOR:
MALE: DEAD AND MORIBUND ANIMALS APPENDIX Q 3 HISTOPATHOLOGICAL FINDINGS: METASTASIS OF TUMOR:
MALE: SACRIFICED ANIMALS APPENDIX Q 4 HISTOPATHOLOGICAL FINDINGS: METASTASIS OF TUMOR:
FEMALE: ALL ANIMALS APPENDIX Q 5 HISTOPATHOLOGICAL FINDINGS: METASTASIS OF TUMOR:
FEMALE: DEAD AND MORIBUND ANIMALS APPENDIX Q 6 HISTOPATHOLOGICAL FINDINGS: METASTASIS OF TUMOR:
FEMALE: SACRIFICED ANIMALS APPENDIX R METHODS, UNITS AND DECIMAL PLACE FOR HEMATOLOGY
AND BIOCHEMISTRY IN THE 2-YEAR DRINKING WATER STUDY OF METHYL ACETOACETATE
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(Study No. 0449)
APPENDICES (CONTINUED) APPENDIX I 1 URINALYSIS: MALE APPENDIX I 2 URINALYSIS: FEMALE APPENDIX J 1 GROSS FINDINGS: MALE: ALL ANIMALS APPENDIX J 2 GROSS FINDINGS: MALE : DEAD AND MORIBUND ANIMALS APPENDIX J 3 GROSS FINDINGS: MALE: SACRIFICED ANIMALS APPENDIX J 4 GROSS FINDINGS: FEMALE: ALL ANIMALS APPENDIX J 5 GROSS FINDINGS: FEMALE: DEAD AND MORIBUND ANIMALS APPENDIX J 6 GROSS FINDINGS: FEMALE: SACRIFICED ANIMALS APPENDIX K 1 ORGAN WEIGHT, ABSOLUTE: MALE APPENDIX K 2 ORGAN WEIGHT, ABSOLUTE: FEMALE APPENDIX L 1 ORGAN WEIGHT, RELATIVE: MALE APPENDIX L 2 ORGAN WEIGHT, RELATIVE: FEMALE APPENDIX M 1 HISTOPATHOLOGICAL FINDINGS: NON-NEOPLASTIC
LESIONS: MALE: ALL ANIMALS APPENDIX M 2 HISTOPATHOLOGICAL FINDINGS: NON-NEOPLASTIC
LESIONS: MALE: DEAD AND MORIBUND ANIMALS APPENDIX M 3 HISTOPATHOLOGICAL FINDINGS: NON-NEOPLASTIC
LESIONS: MALE: SACRIFICED ANIMALS APPENDIX M 4 HISTOPATHOLOGICAL FINDINGS: NON-NEOPLASTIC
LESIONS: FEMALE: ALL ANIMALS APPENDIX M 5 HISTOPATHOLOGICAL FINDINGS: NON-NEOPLASTIC
LESIONS: FEMALE: DEAD AND MORIBUND ANIMALS APPENDIX M 6 HISTOPATHOLOGICAL FINDINGS: NON-NEOPLASTIC
LESIONS: FEMALE: SACRIFICED ANIMALS
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APPENDIX A 1
IDENTITY OF METHYL ACETOACETATE
IN THE 2-YEAR DRINKING WATER STUDY
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(Study No. 0449)
IDENTITY OF METHYL ACETOACETATE IN THE 2-YEAR DRINKING WATER STUDY Test Substance : Methyl Acetoacetate (Tokyo Kasei Kogyo Co., Ltd.) A. Lot No. : GL01 1. Spectral Data Mass Spectrometry Instrument : Hewlett Packard 5989B Mass Spectrometer Ionization : EI (Electron Ionization) Ionization Voltage : 70eV
10 20 30 40 50 60 70 80 90 100 110 1200 200000 400000 600000 800000
1000000 1200000 1400000 1600000 1800000 2000000
m/z-->
Abundance
15
43
59
69
85
101
116
Mass Spectrum of Test Substance
10 20 30 40 50 60 70 80 90 100 110 1200
1000
2000
3000
4000
5000
6000
7000
8000
9000
m/z-->
Abundance
15
43
5969
85
101
116
Mass Spectrum of Literature Data*
Result: The mass spectrum was consistent with literature spectrum. (*McLafferty FW, ed. 1994. Wiley Registry of Mass Spectral Data. 6th ed. New York, NY:John Wiley and Sons.)
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(Study No. 0449)
Infrared Spectrometry Instrument : Shimadzu FTIR-8200PC Infrared Spectrometer Cell : KBr Liquid Cell Resolution : 2 cm-1
0.0
25.0
50.0
75.0
100.0
%T
500.01000.01500.02000.03000.04000.0
1cm-1 Infrared Spectrum of Test Substance
Infrared Spectrum of Literature Data* Result: The infrared spectrum was consistent with literature spectrum. (*Simons WW. 1978. The Sadtler Handbook of Infrared Spectra. Philadelphia, PV : Sadtler Research Laboratories, 766) 2. Conclusion: The test substance was identified as methyl acetoacetate by mass spectrum and infrared spectrum.
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(Study No. 0449)
B. Lot No. : FGL01 1. Spectral Data Mass Spectrometry Instrument : Hewlett Packard 5989B Mass Spectrometer Ionization : EI (Electron Ionization) Ionization Voltage : 70eV
10 20 30 40 50 60 70 80 90 100 110 1200
200000
400000
600000
800000
1000000
1200000
1400000
1600000
m/z-->
Abundance
15
43
59
69
85
101
116
Mass Spectrum of Test Substance
10 20 30 40 50 60 70 80 90 100 110 1200
1000
2000
3000
4000
5000
6000
7000
8000
9000
m/z-->
Abundance
15
43
5969
85
101
116
Mass Spectrum of Literature Data*
Result: The mass spectrum was consistent with literature spectrum. (*McLafferty FW, ed. 1994. Wiley Registry of Mass Spectral Data. 6th ed. New York, NY:John Wiley and Sons.)
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(Study No. 0449)
Infrared Spectrometry Instrument : Shimadzu FTIR-8200PC Infrared Spectrometer Cell : KBr Liquid Cell Resolution : 2 cm-1
0.0
25.0
50.0
75.0
100.0
%T
500.01000.01500.02000.03000.04000.0
1cm-1 Infrared Spectrum of Test Substance
Infrared Spectrum of Literature Data* Result: The infrared spectrum was consistent with literature spectrum. (*Simons WW. 1978. The Sadtler Handbook of Infrared Spectra. Philadelphia, PV : Sadtler Research Laboratories, 766) 2. Conclusion: The test substance was identified as methyl acetoacetate by mass spectrum and infrared spectrum.
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APPENDIX A 2
STABILITY OF METHYL ACETOACETATE
IN THE 2-YEAR DRINKING WATER STUDY
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(Study No. 0449)
STABILITY OF METHYL ACETOACETATE IN THE 2-YEAR DRINKING WATER STUDY Test Substance : Methyl Acetoacetate (Tokyo Kasei Kogyo Co., Ltd.) A. Lot No. : GL01 1. Sample : This lot was used from 2002.3.21 to 2003.6.30. The test substance was stored in a dark place at room temperature. 2. Gas Chromatography Instrument : Hewlett Packard 5890A Gas Chromatograph Column : INNOWAX (0.2 mmφ 50 m) Column Temperature : 100 ゚C (1 min) → (10 ℃/min) → 190 ゚C Flow Rate : 1 mL/min Detector : FID (Flame Ionization Detector) Injection Volume : 1 L Date Peak No. Retention Time Area (date analyzed) (min) (%) 2002.03.13 1 6.578 100 2003.07.03 1 6.581 100
Result: Gas chromatography indicated one major peak (peak No.1) analyzed at 2002.3.13 and one major peak (peak No.1) analyzed at 2003.7.3. No new trace impurity peak in the test substance analyzed at 2003.7.3 was detected.
3. Conclusion: The test substance was stable for about 16 months in a dark place at room temperature.
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(Study No. 0449)
B. Lot No. : FGL01 1. Sample : This lot was used from 2003.6.30 to 2004.3.25. The test substance was stored in a dark place at room temperature. 2. Gas Chromatography Instrument : Hewlett Packard 5890A Gas Chromatograph Column : INNOWAX (0.2 mmφ 50 m) Column Temperature : 100 ゚C (1 min) → (10 ℃/min) → 190 ゚C Flow Rate : 1 mL/min Detector : FID (Flame Ionization Detector) Injection Volume : 1 L Date Peak No. Retention Time Area (date analyzed) (min) (%) 2003.06.19 1 6.585 100 2004.04.20 1 6.584 100
Result: Gas chromatography indicated one major peak (peak No.1) analyzed at 2003.6.19 and one major peak (peak No.1) analyzed at 2004.4.20. No new trace impurity peak in the test substance analyzed at 2004.4.20 was detected.
3. Conclusion: The test substance was stable for about 10 months in a dark place at room temperature.
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APPENDIX A 3
CONCENTRATION OF METHYL ACETOACETATE
IN FORMULATED WATER IN THE 2-YEAR
DRINKING WATER STUDY
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CONCENTRATION OF METHYL ACETOACETATE IN FORMULATED WATER IN THE 2-YEAR DRINKING WATER STUDY
Target Concentration
Date Analyzed 2000a 6325 20000
2002.03.21 2020 (101)b 6430 (102) 20300 (102) 2002.06.13 2000 (100) 6320 ( 99.9) 20100 (101) 2002.09.05 2100 (105) 6630 (105) 21100 (106) 2002.11.28 2040 (102) 6540 (103) 20900 (105) 2003.02.20 2030 (102) 6560 (104) 21200 (106) 2003.05.15 1970 ( 98.5) 6360 (101) 20300 (102) 2003.08.07 1980 ( 99.0) 6350 (100) 20300 (102) 2003.10.30 2010 (101) 6480 (102) 20800 (104) 2004.01.22 2020 (101) 6260 ( 99.0) 19900 ( 99.5)
a ppm b %
Analytical Method : The samples were analyzed by gas chromatography. Instrument : Hewlett Packard 5890A Gas Chromatograph Column : INNOWAX (0.2 mmφ 50 m) Column Temperature : 100 ゚C (1 min) → (10 ℃/min) → 190 ゚C Flow Rate : 1 mL/min Detector : FID (Flame Ionization Detector) Injection Volume : 1 L (Study
No.
0449)
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APPENDIX A 4
STABILITY OF METHYL ACETOACETATE
IN FORMULATED WATER IN THE 2-YEAR
DRINKING WATER STUDY
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STABILITY OF METHYL ACETOACETATE IN FORMULATED WATER IN THE 2-YEAR DRINKING WATER STUDY
Target Concentration
Date Prepared Date Analyzed 2000a 20000
2002.03.07 2002.03.07 1990 (100)b 20200 (100) 2002.03.11c 2000 (101) 19900 ( 98.5) 2002.03.15c 2000 (101) 19300 ( 95.5) 2002.03.19c 2030 (102) 19500 ( 96.5)
a ppm b % (Percentage was based on the concentration on date of preparation.) c Animal room samples
Analytical Method : The samples were analyzed by gas chromatography. Instrument : Hewlett Packard 5890A Gas Chromatograph Column : INNOWAX (0.2 mmφ 50 m) Column Temperature : 100 ゚C (1 min) → (10 ℃/min) → 190 ゚C Flow Rate : 1 mL/min Detector : FID (Flame Ionization Detector) Injection Volume : 1 L
(StudyN
o.0449)
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APPENDIX B 1
CLINICAL OBSERVATION : MALE
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APPENDIX B 2
CLINICAL OBSERVATION : FEMALE
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APPENDIX C 1
BODY WEIGHT CHANGES : MALE
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APPENDIX C 2
BODY WEIGHT CHANGES : FEMALE
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APPENDIX D 1
FOOD CONSUMPTION CHANGES : MALE
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APPENDIX D 2
FOOD CONSUMPTION CHANGES : FEMALE
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APPENDIX E 1
WATER CONSUMPTION CHANGES : MALE
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APPENDIX E 2
WATER CONSUMPTION CHANGES : FEMALE
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APPENDIX F 1
CHEMICAL INTAKE CHANGES : MALE
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APPENDIX F 2
CHEMICAL INTAKE CHANGES : FEMALE
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APPENDIX G 1
HEMATOLOGY : MALE
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APPENDIX G 2
HEMATOLOGY : FEMALE
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APPENDIX H 1
BIOCHEMISTRY : MALE
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APPENDIX H 2
BIOCHEMISTRY : FEMALE
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APPENDIX I 1
URINALYSIS : MALE
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APPENDIX I 2
URINALYSIS : FEMALE
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APPENDIX J 1
GROSS FINDINGS : MALE
ALL ANIMALS
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APPENDIX J 2
GROSS FINDINGS : MALE
DEAD AND MORIBUND ANIMALS
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APPENDIX J 3
GROSS FINDINGS : MALE
SACRIFICED ANIMALS
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APPENDIX J 4
GROSS FINDINGS : FEMALE
ALL ANIMALS
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APPENDIX J 5
GROSS FINDINGS : FEMALE
DEAD AND MORIBUND ANIMALS
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APPENDIX J 6
GROSS FINDINGS : FEMALE
SACRIFICED ANIMALS
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APPENDIX K 1
ORGAN WEIGHT, ABSOLUTE : MALE
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APPENDIX L 2
ORGAN WEIGHT, RELATIVE : FEMALE
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APPENDIX L 1
ORGAN WEIGHT, RELATIVE : MALE
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APPENDIX K 2
ORGAN WEIGHT, ABSOLUTE : FEMALE
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APPENDIX M 1
HISTOPATHOLOGICAL FINDINGS :
NON-NEOPLASTIC LESIONS : MALE
ALL ANIMALS
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APPENDIX M 2
HISTOPATHOLOGICAL FINDINGS :
NON-NEOPLASTIC LESIONS : MALE
DEAD AND MORIBUND ANIMALS
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APPENDIX M 3
HISTOPATHOLOGICAL FINDINGS :
NON-NEOPLASTIC LESIONS : MALE
SACRIFICED ANIMALS
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APPENDIX M 4
HISTOPATHOLOGICAL FINDINGS :
NON-NEOPLASTIC LESIONS : FEMALE
ALL ANIMALS
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APPENDIX M 5
HISTOPATHOLOGICAL FINDINGS :
NON-NEOPLASTIC LESIONS : FEMALE
DEAD AND MORIBUND ANIMALS
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APPENDIX M 6
HISTOPATHOLOGICAL FINDINGS :
NON-NEOPLASTIC LESIONS : FEMALE
SACRIFICED ANIMALS
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APPENDIX N 1
NUMBER OF ANIMALS WITH TUMORS
AND NUMBER OF TUMORS-TIME RELATED : MALE
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APPENDIX N 2
NUMBER OF ANIMALS WITH TUMORS
AND NUMBER OF TUMORS-TIME RELATED : FEMALE
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APPENDIX O 1
HISTOPATHOLOGICAL FINDINGS :
NEOPLASTIC LESIONS : MALE
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APPENDIX O 2
HISTOPATHOLOGICAL FINDINGS :
NEOPLASTIC LESIONS : FEMALE
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APPENDIX P 1
NEOPLASTIC LESIONS-INCIDENCE
AND STATISTICAL ANALYSIS : MALE
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APPENDIX P 2
NEOPLASTIC LESIONS-INCIDENCE
AND STATISTICAL ANALYSIS : FEMALE
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APPENDIX Q 1
HISTOPATHOLOGICAL FINDINGS: METASTASIS OF TUMOR:
MALE : ALL ANIMALS
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APPENDIX Q 2
HISTOPATHOLOGICAL FINDINGS: METASTASIS OF TUMOR:
MALE : DEAD AND MORIBUND ANIMALS
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APPENDIX Q 3
HISTOPATHOLOGICAL FINDINGS: METASTASIS OF TUMOR:
MALE : SACRIFICED ANIMALS
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APPENDIX Q 4
HISTOPATHOLOGICAL FINDINGS: METASTASIS OF TUMOR:
FEMALE : ALL ANIMALS
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APPENDIX Q 5
HISTOPATHOLOGICAL FINDINGS: METASTASIS OF TUMOR:
FEMALE : DEAD AND MORIBUND ANIMALS
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APPENDIX Q 6
HISTOPATHOLOGICAL FINDINGS: METASTASIS OF TUMOR:
FEMALE : SACRIFICED ANIMALS
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APPENDIX R
METHODS, UNITS AND DECIMAL PLACE FOR
HEMATOLOGY AND BIOCHEMISTRY IN THE 2-YEAR
DRINKING WATER STUDY OF METHYL ACETOACETATE